It is now well established that the Ca++ ion plays a central role in the process of excitation-contraction coupling in the heart. The general purpose of this study is to evaluate the abnormalities in excitation-contraction coupling that occur in cardiac hypertrophy and failure in experimental animals and man, and to determine the effects of potential therapeutic interventions on hypertophied heart muscle. A large amount of information has accumulated to suggest that intracellular Ca++ handling is abnormal in cardiac hypertrophy, with or without the onset of failure. By use of aequorin, a bioluminescent calcium indicator that emits light when it combines with Ca++, it is possible to directly record intracellular Ca++ transients during contraction and relaxation of cardia muscle fibers. Aequorin will be used to determine how changes in intracellular Ca++ handling are related to the mechanical and electrical abnormalities that occur with hypertrophy and hypoxia of mammalian working myocardium. The subcellular actions of inotropic agents on intracellular Ca++ transients in hypertrophied cardiac muscle will be studied, including the triggerable activity that occurs with toxic doses of these agents. Papillary muscles and isolated myocytes from control and hypertrophied ferrets and hamsters will be loaded with aequorin; light (i.e., intracellular Ca++,) tension and electrical activity will be recorded. Human working myocardium removed at the time of cardiac surgery from patients with hypertrophy will also be studied. The aequorin signals from intact muscle will be correlated with Ca++ handling by isolated sarcoplasmic recticulum vesicles. By directly recording intracellular Ca++ transients in intact and actively contracting cardiac fibers that are hypoxic or hypertrophied, it will be possible for the first time to test the functional significance of the subcellular abnormalities in intracellular Ca++ handling that have been reported by other investigators, particularly with regard to the function of the sarcoplasmic reticulum. In addition, these studies will provide new information of clinical importance regarding the therapeuitc and toxic effects of inotropic drugs on hypertrophied cardiac muscles, and, in the long-term, should help to define the role of Ca++ in the pathogenesis of the hypertrophic response. Moreover, these studies will lay the groundwork for the use of intracellular calcium indicators as diagnostic and prognostic tools in clinical medicine.